6.1 BIOEQUIVALENCE STUDIES used to teach in Pharmaceuticals (final).pptx

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BIOEQUIVALENCE
STUDIES
UNIVERSITY OF CENTRAL PUNJAB

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CONTENTS
 BE Definition
 HISTORY
 ORANGE BOOK
 WHAT ARE GENERIC DRUGS?
 OBJECTIVES OF BA & BE STUDIES
 NEED FOR BIOEQUIVALENCE
 BE CONCEPT
 STUDY METHOD
 TYPES OF BE STUDIES
 BE STUDY PROTOCOL
 TYPES OF TEST DESIGNS
 RETENTION OF BA/BE STUDIES
 EVALUATION OF THE DATA
 CONCLUSION

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BIOEQUIVALENCE
 DEFINITION:
“The absence of a significant difference in the
rate and extent to which the active ingredient or
active moiety in pharmaceutical equivalents or
pharmaceutical alternatives becomes available at
the site of drug action when administered at the
same molar dose under similar conditions in an
appropriately designed study.”

UNIVERSITY OF CENTRAL PUNJAB 4
BIOEQUIVALENCE-ASSUMPTION
SAME BA
PROFILE
SAME
AMOUNT
OF DRUG
AT SITE OF
DRUG
ACTION
THERAPEUTICAL
EQUIVALENCE

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ORANGE BOOK
 All FDA approved drug products listed (NDA’s, OTC’s &
ANDA’s)
 Therapeutic equivalence codes
 “A” = Substitutable
 “B” = In-equivalent, NOT Substitutable
 Reference Listed Drugs/ brand drugs identified by FDA for
generic companies to compare with their proposed
products
 http://www.fda.gov/downloads/Training/ForHealthProfessionals/ucm090413.ppt

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WHAT ARE GENERIC DRUG?
• Compare with Original Drug (Brand Drug) to have the:
1. Same active ingredient(s)
2. Quantities
3. Route of administration
4. Dosage form
5. Direction and dose
6. Indications and effects
• Can be used similarly as brand drug.
• May have different:
1. Excipients
2. Color
3. Shape

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REQUIREMENTS/ OBJECTIVES
 If a new product is intended to be a substitute for an approved
medicinal product as a pharmaceutical equivalent or
alternative, the equivalence with this product should be shown
or justified.
 In order to ensure clinical performance of such drug products,
BE studies should be performed.
 BE studies are conducted if there is:
 A risk of Bio-inequivalence and/ or
 A risk of pharmacotherapeutic failure or diminished clinical
safety.
 http://www.slideshare.net/sujitpatel11/bioequivalence-studies?

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OBJECTIVES OF BA & BE STUDIES
 Development of suitable dosage form for a new drug entity.
 Determination of influence of excipients, patient related
factors & possible interactions with other drugs.
 Development of new drug formulations of existing drugs.
 Control of quality of drug products, influence of processing
factors, storage & stability.
 Comparison of availability of a drug substance from
different forms or same dosage form produced by different
manufacturers.

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IMPORTANT TERMS
 EQUIVALENCE:
It is a relative term that compares drug products with
respect to a specific characteristic or function or to a defined
set of standards.
 There are several types of equivalences:
A) Chemical Equivalent
B) Pharmaceutical Equivalent
C) Therapeutic Equivalent
D) Bioequivalent

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IMPORTANT TERMS
A) CHEMICAL EQUIVALENT:
It indicates that two or more drug products contain the
same labeled chemical substance as an active ingredient in
the same amount.
B) PHARMACEUTICAL EQUIVALENT:
This term implies that two or more drug products are
identical in strength, quality, purity, content uniformity,
disintegration & dissolution characteristics. They may,
however, differ in containing different excipients.

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IMPORTANT TERMS
C) THERAPEUTIC EQUIVALENT:
It indicates that two or more drug products that contain
the same therapeutically active ingredient elicit
identical pharmacological effects & can control the
disease to the same extent.
D) BIOEQUIVALENT:
It refers to the drug substance in two or more identical
dosage forms, reaches systemic circulation at the same rate
and to the same relative extent.

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BIOEQUIVALENCE CONCEPTS
Close concentration profiles close effects
Concentrations
Time
Effects Exposure
pioneer
generic
Close PK
parameters
AUC, Cmax
Tmax
Cmax

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BIOEQUIVALENCE CONCEPTS
 BE studies should be conducted for the comparison of
two medicinal products containing the same active
substance.
 The studies should provide an objective means of
critically assessing the possibility of alternative use of
them.
 Two products marketed by different licenses,
containing same active ingredient(s), must be shown to
be therapeutically equivalent to one another in order to
be considered interchangeable.

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BIOEQUIVALENCE CONCEPT
Reference Test
Pharmaceutical Equivalent
Products
Possible Differences
Drug particle size, ..
Excipients
Manufacturing process
Equipment
Site of manufacture
Batch size ….
Documented Bioequivalence = Therapeutic Equivalence
(Note: Generally, same dissolution specifications)

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BIOEQUIVALENCE
 Important PK parameters
AUC: area under the concentration-time curve 
measure of the extent of absorption
Cmax: the observed maximum conc. of a drug 
measure of the rate of absorption
Tmax: time at which Cmax is observed 
measure of the rate of absorption

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STUDY METHODS
Different approaches for
establishing equivalence
PD studies
clinical
studies
In-vitro
methods

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1..PHARMACODYNAMICS STUDY
Comparative
PD studies
In case of local action/no
systemic absorption
Not recommended when:
 active ingredient is absorbed into the systemic circulation
 pharmacokinetic study can be conducted

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2..CLINICAL STUDIES
Comparative
clinical studies
in case PK or PD studies can
not be performed
 If bioequivalence studies and pharmacodynamic studies
are inappropriate, this study is applied.
 The Acceptance criteria of equivalence in this study
should be pharmacological characteristics and activity of
each drug.
Guideline for Bioequivalence Studies of Generic Products
http://www.nihs.go.jp/drug/be-guide(e)/Generic/be97E.pdf

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TYPES OF BIOEQUIVALENCE STUDIES
Bioequivalence can be demonstrated either;
 In-Vivo
or
 In-Vitro
IN-VIVO BIOEQUIVALENCE STUDIES:
 The following sequence of criteria is useful in assessing the
need for in-vivo studies:
1. Oral immediate-release products with systemic action;
 Indicated for serious conditions requiring assured
response.
 Narrow therapeutic margin.
 Pk complicated by absorption < 70%, non linear kinetics

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IN-VIVO BIOEQUIVALENCE STUDIES
 Unfavorable physiochemical properties, e.g. low solubility,
instability etc.
 Documented evidence for BA problems.
 No relevant data available, unless justification by applicant
that in-vivo study is not necessary.
2. Non oral immediate-release products.
3. Modified release products with systemic action.

 In-vivo BE studies are conducted in the usual manner
as for BA studies i.e. the pharmacokinetic and the
pharmacodynamic methods.
1. Pk METHODS:
a) Plasma level-time studies
b) Urinary Excretion studies
2. PD METHODS
a) Acute pharmacological response
b) Therapeutic response
IN-VIVO BIOEQUIVALENCE STUDIES

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 If none of the above criteria is applicable, comparative in-vitro
Dissolution studies will suffice.
 In-vitro studies, i.e. Dissolution studies can be used in place of in-vivo
BE under certain circumstances, called as Biowavers (exemptions)
1. The drug product differs only in strength of the active substance
it contains, provided all the following conditions hold-
 Pks are linear.
 The qualitative composition is same.
 The ratio b/w active substance and the excipients is the same.
 Both products are produced by the same manufacturer at the same
production site.
 A BA or BE study has been performed with an original product.
 Under the same test conditions, the in-vitro dissolution rate is the
same.
IN-VITRO BIOEQUIVALENCE STUDIES

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IN-VITRO BIOEQUIVALENCE STUDIES
2. The drug product meets all of the following
requirements:
 The product is in the form of solution or solubilised
form.
 The product contains AI in the same concentration as the
approved drug product.
 The products contain no excipients known to
significantly affect absorption of AI.
 In-vitro dissolution rate of new product is equivalent
with that of already approved medicinal product.
 Biopharmaceutics & Pharmacokinetics – Treatise by D.M. BRAHMANKAR,
SUNIL B. JAISWAL

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BE STUDY PROTOCOL
1…TITLE:
a) Principle investigator (study director)
b) Project/ protocol number and date
2… STUDY OBJECTIVE:
3… STUDY DESIGN:
a) Design
b) Drug product
4… SUBJECT SELECTION/ TREATMENT:
c) Medical history
d) Physical examination
e) Lab tests

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BE STUDY PROTOCOL
5…CLINICAL PROCEDURES/ EXPERIMENTAL
TECHNIQUE:
a) Dosage & drug administration
b) Biological sampling schedule
c) Activity of subjects
6…ETHICAL CONSIDERATIONS:
7…FACILITIES
8…DATAANALYSIS
9…ANALYTICAL VALIDATION PROCEDURE
10.. APPENDIX

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TYPES OF TEST DESIGNS
1.. COMPLETELY RANDOMISED DESIGNS:
All treatments are randomly allocated among all experimental
subjects.
METHOD OF RANDOMIZATION:
Label all subjects with same number digits. Randomly select non-
repeating numbers.
ADVANTAGES:
 Easy to construct.
 Any number of treatments & subjects.
 Easy & simple to analyze
DISADVANTAGES:
 Best suited for relatively few treatments.

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2.. RANDOMIZED BLOCK DESIGNS:
Subjects are sorted into homogeneous groups called blocks.
METHOD OF RANDOMIZATION:
 Subject having similar background characteristics are
formed as blocks.
 Then treatments are randomized within each block, just like
the simple randomization.
ADVANTAGES:
 Effective & systematic way of grouping
 Different treatments does not need equal sample size
DISADVANTAGES:
 More complex analysis

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3.. REPEATED MEASURES, CROSS-OVER & CARRY-OUT
DESIGNS:
 Same subject served as a block.
 Repeated measures on each subject, we get the design name repeated
measure design.
 The administration of 2 or more treatments one after the other in a
specific or random order to the same group of patients is called Cross-
over design or Change-over design.
ADVANTAGES:
 Good precision for comparing treatments.
4.. LATIN-SQUARE DESIGN:
 Each subject receives each treatment during the course of experiment.
 A Latin-square design is a 2 factor design with one observation in
each cell.

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 Rows represent subject and column represent treatment
 Compare 3 different drug formulations- A,B, & C.
 In this design, each subject receives each drug product only
once.
Subject Study period 1 Study period 2 Study period 3
1 A B C
2 C A B
3 A C B
4 A C B
5 C B A
6 B A C

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TYPES OF TEST DESIGN
ADVANTAGES:
 Minimizes time effect
 It requires less number of subject to get meaningful results.
DISADVANTAGES:
 Degree of freedom for experimental error is larger than necessary.
 More complex.
 Applied Biopharmaceutics and pharmacokinetics by LEON SHARGEL

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EVALUATION OF THE DATA
ANALYTICAL METHOD:
 The analytical method for measurement of drug must be
validated for accuracy, precision sensitivity and specificity.
 Only 1 analytical method is used during bioequivalence
study because different method may yield different values.
 Data should be presented in both graphical and tabulated
form for evaluation.
PHARMACOKINETIC EVALUATION OF DATA:
1.. For single dose studies:
 Pharmacokinetic analysis include calculation of AUC,
C-max, T-max.
2.. For multiple dose:
 Calculation of steady state AUC, T-max, C-max , C-min

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EVALUATION OF THE DATA
STATISTICAL EVALUATION OF THE DATA:
 This can be done by using analysis of variance (ANOVA)
test.
 An analysis of variance is a statistical procedure used to test
the data for differences within and between treatment and
control groups.
 Applied Biopharmaceutics and pharmacokinetics by LEON SHARGEL

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RETENTION OF BA/ BE STUDIES
 All samples (test and reference drug product) should be
retained by an organization carrying out BA/BE study for 3
years after the conduct of study or 1 year after the expiry of the
drug whichever is earlier.
MAINTENANCE OF RECORDS OF BA/BE STUDIES:
 Record must be maintained for at least 2 years after the
expiration date of the batch.
 Goodman’s & Gilman’s, the pharmacological basis of therapeutics, 12th
edition
 Essentials in pharmacology, K.D. Tripathi, 6th
edition
 Principles of pharmacology, HL Sharma, 2nd
edition

DISSOLUTION STUDIES
1. Suitable to confirm unchanged product quality with minor
changes in formulation / manufacturing after approval →
SUPAC ( Scale-Up & Post-Approval Changes)
2. Different strengths of drug manufactured by same
manufacturer where:
• Qualitative composition is same
• Ratio of active ingredients & excipients is same
• Method of manufacture is same
• BE study has been performed on 1 strength
• Linear pharmacokinetics
3. Signal of bio-inequivalence
4. Assess batch-to-batch quality
 More than 1 batch of each formulation tested

DESIGN SHOULD INCLUDE
 Individually testing of at least 12 dosage units of each
batch →Mean & Individual results with Sd or SE
 Measurement of percentage of content released at
suitably spaced time points
(e.g. At 10, 20 & 30 mins or appropriate for complete
dissolution)
 Dissolution profile in at least 3 aqueous media with pH
range of 1.0 - 6.8 or 1.0 - 8.0 wherever necessary
 Conduct tests on each batch with same apparatus & on
same or consecutive days

DISSOLUTION TESTING SHOULD BE CARRIED OUT IN:
 USP Apparatus-I at 100 rpm or Apparatus-II at 50 rpm
using 900 ml of the following dissolution media:
• 0.1N HCl or Simulated Gastric Fluid USP without
enzymes
• a pH 4.5 buffer
• a pH 6.8 buffer or Simulated Intestinal Fluid USP
without enzymes
 For capsules and tablets with gelatin coating
• Simulated Gastric and Intestinal Fluids USP (with
enzymes) can be used

ADVANTAGES OFFERED
 Reduced costs:
• Data anticipates Bioequivalence
• Type II error ++ for PK studies
 More direct assessment:
• If complicated in-vivo assessment
 Ethical benefit:
• No unnecessary human study

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CONCLUSION
o Concept of BE has been adopted by the pharmaceutical
industry and national regulatory authorities throughout the
world for over 20 years.
o There is a continuing attempt to understand and develop
more efficient and scientifically valid approaches to assess
BE of various dosage forms.
o Generics help patients by making drugs available at
affordable price while retaining their quality.
o Balance public interests especially in diseases like cancer &
AIDs which have high prevalence in developing countries.
o Generic drugs are safe and effective equal to brand name
prescriptions.
o Generic drugs can help both consumers and the
governments in reducing the cost of prescription drugs.

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REFERENCES
1. Essentials in pharmacology, K.D. Tripathi, 6th
edition
2. Goodman’s & Gilman’s, the pharmacological basis of therapeutics, 12th
edition
3. Principles of pharmacology, HL Sharma, 2nd
edition
4. Biopharmaceutics & Pharmacokinetics – Treatise by D.M. BRAHMANKAR,
SUNIL B. JAISWAL
5. Text book of biopharmaceutics & pharmacokinetics by V.VENKATESWARLU
6. Applied biopharmaceutics & pharmacokinetics by LEON SHARGEL
7. Guideline for Bioequivalence Studies of Generic Product
http://www.nihs.go.jp/drug/be-guide(e)/Generic/be97E.pdf
8. http://www.fda.gov
9. http://www.biostat.envt.fr/spip/IMG/ppt/BE_Workshop_2010.ppt
10. http://www.amstat.org/chapters/boston/IBE_1202_2003.ppt
11. http://www.fda.gov/downloads/Training/ForHealthProfessionals/ucm090413.ppt
NIVERSITY OF CENTRAL PUNJAB

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